title: Pulmonary vein stenosis and the pathophysiology of "upstream" pulmonary veins.
abstract: BACKGROUND
  Surgical and catheter-based interventions on pulmonary veins are associated with pulmonary vein stenosis (PVS), which can progress diffusely through the "upstream" pulmonary veins. The mechanism has been rarely studied. We used a porcine model of PVS to assess disease progression with emphasis on the potential role of endothelial-mesenchymal transition (EndMT).
  
  
  METHODS
  Neonatal piglets underwent bilateral pulmonary vein banding (banded, n = 6) or sham operations (sham, n = 6). Additional piglets underwent identical banding and stent implantation in a single-banded pulmonary vein 3 weeks postbanding (stented, n = 6). At 7 weeks postbanding, hemodynamics and upstream PV pathology were assessed.
  
  
  RESULTS
  Banded piglets developed pulmonary hypertension. The upstream pulmonary veins exhibited intimal thickening associated with features of EndMT, including increased transforming growth factor (TGF)-β1 and Smad expression, loss of endothelial and gain of mesenchymal marker expression, and coexpression of endothelial and mesenchymal markers in banded pulmonary vein intimal cells. These immunopathologic changes and a prominent myofibroblast phenotype in the remodeled pulmonary veins were consistently identified in specimens from patients with PVS, in vitro TGF-β1-stimulated cells isolated from piglet and human pulmonary veins, and human umbilical vein endothelial cells. After stent implantation, decompression of a pulmonary vein was associated with reappearance of endothelial marker expression, suggesting the potential for plasticity in the observed pathologic changes, followed by rapid in-stent restenosis.
  
  
  CONCLUSIONS
  Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yaqin Yana
authors.initials: YY
authors.lastname: Fu
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lixing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shabana
authors.initials: S
authors.lastname: Aafaqi
authors.affiliation: Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Otto
authors.initials: O
authors.lastname: Rahkonen
authors.affiliation: Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Cameron
authors.initials: C
authors.lastname: Slorach
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Traister
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chung Ho
authors.initials: CH
authors.lastname: Leung
authors.affiliation: Division of Pathology and Paediatric Laboratory Medicine, Laboratory of Tissue Repair and Regeneration, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chiasson
authors.affiliation: Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Mertens
authors.affiliation: Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Benson
authors.affiliation: Division of Cardiac Surgery, Toronto General Hospital, Toronto, Ontario, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Division of Anaesthesia and Pain Medicine and Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Maynes
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada.
authors.forename: John G
authors.initials: JG
authors.lastname: Coles
authors.affiliation: Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center and University of Toronto, Toronto, Ontario, Canada. Electronic address: christopher.caldarone@sickkids.ca.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Caldarone
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006439:Hemodynamics; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011668:Pulmonary Veno-Occlusive Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D012008:Recurrence; D051785:Smad Proteins / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1